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Effects of anti-IL17 on inflammation, remodeling oxidative stress in an ASMA-COPD Overlay Syndrome (ACOS) model

Grant number: 19/26449-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): February 01, 2020
Effective date (End): January 31, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Iolanda de Fátima Lopes Calvo Tibério
Grantee:Francine Maria de Almeida
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/02537-5 - Characterization of asthma-COPD overlap syndrome (ACOS): experimental and clinical studies, AP.TEM

Abstract

Recent studies have shown that IL-17 plays a role in eosinophil, macrophage and neutrophil signaling and recruitment, especially in Asthma and COPD. Therefore, the hypothesis is that inhibition of this interleukin will be able to reduce inflammation, remodeling and oxidative stress in an experimental model of ACOS, acting as a therapeutic alternative. Objectives description: to study the effects of anti-IL-17 on pulmonary mechanics in vivo in an experimental model of ACOS, evaluating in the airways and pulmonary parenchyma: A) the recruitment of eosinophils, neutrophils and macrophages; B) extracellular matrix elements: elastic fibers and collagen fibers, actin and TGF-beta; C) cellular expression of MMP-9, MMP-12 and TIMP-1; D) the oxidative stress response: iNOS and 8-iso-PGF-2±; F) cellular expression of proinflammatory (TNF-± and IL-6), anti-inflammatory (IFN-³ and IL-10) and lymphokines (IL-1², IL-2, IL-4, IL-5, IL-8 (KC), IL-13 and IL-17); G) NFºB cell expression. Work plan including methodology and schedule of expected results: male BALB/c mice will be subjected to the experimental protocol for Asthma, Emphysema and ACOS. Parts of these animals will be treated with anti-IL17 in order to understand if this signaling pathway is involved in the responses found in this disease. After the experimental protocol we will evaluate inflammation, oxidative stress and remodeling of the extracellular matrix of the airways and pulmonary parenchyma. Inflammation will be assessed by ELISA, remodeling by morphometric analysis and image analyzer and cell signaling pathways as NFºB by Blotting. Rationale for the plan: COPD and Asthma are chronic inflammatory diseases that affect the airways and lung parenchyma and are essentially characterized by the presence of bronchial obstruction, but are diseases with different etiopathogenic and diagnostic bases and have therapeutic and therapeutic characteristics. prognostic. However, some patients are unresponsive to corticosteroid treatment and may present characteristics of both diseases and this condition has been called Asthma Overlap Syndrome and COPD (ACOS). There are several studies in the literature showing the action of IL17 on acute and chronic inflammatory processes, but none addressed the role of IL17 in the inflammatory modulation of ACOS. Therefore, in this study we will address the role of IL17 in the pathophysiology of this disease, as well as a possible therapeutic target using anti-IL17. The proposed project schedule is in accordance with the period provided by FMUSP for the postdoctoral program (two years) and the proposed methodologies are adequate to the postdoctoral requirements, integrating all the techniques used in the host laboratory of this study. (morphometric analysis, immunohistochemistry, image analyzer, ELISA and immunoblotting). (AU)